This proposal investigates mechanisms by which volatile-anesthetics depress normal myocardial activity and cause abnormal skeletal and cardiac nuscle activation in malignant hyperthermia. Halothane usually depresses myocardial activity but it causes severe contractions of muscle in malignant hyperthermia. In the former case complications arise from compromised myocardial function, in the latter from muscle rigidity and associated hyperthermia. Both effects are common and serious (incidence of malignant hyperthermia is 1/50,000 and mortality is 65%). The site of action of volatile anesthetics on muscles is unknown, though calcium metabolism via excitation-contraction coupling has been implicated. Preliminary data from my lab show that exposure of biopsied malignant hyperthermic muscle to halothane (and enflurane) strongly potentiates tetanic tension but depresses contractility of normal human and rat skeletal and cardiac muscles. Further, reduced extracellular calcium and presence of cobalt or Verapamil (calcium permeability blockers) antagonize the anesthetic-potentiated contractions of hyperthermia muscle. These data strongly suggest the sarcolemma to be a site of action of halothane in producing muscle rigidity. By inference, it is implied that transcellular calcium fluxes are involved in the interaction of anesthetics with the normal myocardium. Isometric tension and transmembrane potential measurements will be used to test the hypothesis that halothane affects membrane permeability to calcium in both normal and hyperthermia muscles. This predicts hyperthermia muscle to be supersensitive to calcium ionophores (X537A, A23178), to produce abnormal action potentials (prolonged and/or with lower threshold) and to have potentiated contractility in presence of halothane. These effects should be blocked by calcium permeability blockers (Verapamil, Co+2, Mn+2). In contrast, normal animal myocardial cell function (action potential, contraction) should be depressed by halothane and this depression should be overcome by ionophores which increase membrane calcium. This study may lead to understanding of cellular events in anesthetic-muscle interactions and hence to effective preventive and crisis intervention measures.